The urea cycle is essential for the detoxification of the increased nitrogen waste generated during the metabolic response to trauma. Arginase I, a key enzyme of the urea cycle, generates L-ornithine and urea from L-arginine. Arginase has gained prime importance with the discovery of a second isoenzyme (arginase II) and the discovery of complex physiologic roles for both arginases. Our laboratory has recently observed a significant increase in arginase activity in macrophages and lymphocytes after surgical trauma in mice. The cause and physiologic effects of increased arginase activity after trauma are unknown and constitute the main focus of this research. This grant proposes the following specific aims: 1) characterize changes in tissue arginases caused by trauma. This aim will test the hypothesis that the pattern of arginase production secondary to trauma is distinct from that caused by endotoxin stimulation. We will evaluate the temporal response of arginase activity after trauma, define the patterns of response of the two isoenzymes, and establish the cells and tissues where it is expressed, 2) Identify "factors" that increase arginase activity in tissues after trauma. This aim will test the hypothesis that specific factors (cytokines and/or hormones) involved in the stress response, increase arginase activity. Using complimentary in-vivo and in-vitro experiments, we will test the effects these factors on arginase activity, gene and protein expression, 3) Determine the effects of increased arginase activity after trauma on the metabolic fate of L-arginine and the potential physiologic consequences. We will evaluate the production of nitric oxide, L-ornithine, polyamines and proline under conditions of increased arginase activity after trauma. We believe that increased arginase activity decreases L-arginine availability for the production of nitric oxide. We expect an increased production of proline and polyamines conducive to an environment that favors cellular proliferation and repair. We plan to perform this project using a surgical trauma model that has been well characterized in the laboratory. This project has significant clinical implications providing important links between the metabolic changes of the stress response and the alterations in L-arginine metabolism described after trauma. The new insights into L-arginine metabolism gained by this study provide a novel approach towards understanding the stress response to trauma. A major strength of this project is that it combines the clinical background of the PI with the expertise of two established scientists. The completion of this grant should provide the basis for development of sound, translational research and the progress of the PI into an independent investigator.